Project Summary This proposal investigates a novel multiparametric photoacoustic (mpPA) sensing of prostate tissue abnormality and cancer aggressiveness and turns this concept into a clinically translatable non-invasive detection and monitoring tool for prostate cancer (PCa). Prostate cancer (PCa) is one of the most common types of cancer and the second leading cause of cancer-related death among men in the United States. Screening and monitoring are critical to both finding PCa in its early stage, when they are easier to treat, and managing cancer treatment. PSA test, rectal exam, and transrectal ultrasound (TRUS) imaging exam are a typical stream of PCa screening. Needle biopsy is performed under ultrasound (US) or/and magnetic resonance image (MRI) guidance as definite diagnosis. However, the prevalence of isoechoic or nearly invisible PCa on US ranges from 25 to 42%, and this makes the procedure more systematic rather than lesion specific. Although MRI-guided biopsy can provide high resolution, the system is not real-time and has limited accessibility due to size and cost. Given the limitations of existing diagnostic methods, there is a need to develop a new imaging modality that provides high sensitivity and specificity on PCa with better accessibility. In this proposal, we envision developing an advanced noninvasive and nonionizing imaging modality that leveraging two distinct and complementary parameters of Prostate-specific membrane antigen (PSMA)-targeted contrast agent and oxygen saturation simultaneously for better identification of aggressive PCa. PSMA is a type II integral membrane protein that shows its expression on the surface of PCa cell, is known for showing high affinity with aggressive rather than indolent tumor. However, the limitation of molecular targeted imaging is the fact that cancer specific antigen is not expressed in all cancer types. In fact, PSMA is not expressed in the aggressive PCa cell line, PC-3. Aside from targeted imaging, hypoxia is considered as an alternative cancer indicator based on physiological state of the tissue. Blood oxygen level-dependent (BOLD) information has an ability to depict clinically significant prostate tumor hypoxia. Our imaging approach is based on photoacoustic (PA) imaging, a hybrid modality combining high contrast of optical contrast with high penetration of US imaging. The proposed mpPA imaging performs simultaneous quantification of targeted molecular agent contrast and oxygen saturation to identify prostate tissue abnormality and cancer aggressiveness. This concept will be integrated with a robot-assisted TRUS system for (1) enhancing specificity and sensitivity in detecting PCa, (2) non-invasive therapeutic monitoring as a cancer management tool, and (3) guiding biopsy with enhanced tumor specificity. We will develop a robot-assisted transrectal imaging system applicable to patients, and we will validate the concept in a canine model. The developed imaging platform possesses an MRI compatibility, which enables interoperative cross-validation.